As for the prognostic role of EC PIK3CA and BRAF, in a study including 586 patients by Barault et al., decreased rates of 3-year survival were associated with mutations of at least one gene among KRAS, BRAF and PIK3CA. A recent report by Tol et al. found that the presence of the BRAF V600E mutation was a negative prognostic marker in 516 patients with metastatic colorectal cancer treated with capecitabine, oxaliplatin, and bevacizumab based regimens. Finally, Ogino et al. reported that, in a series of 450 patients with stage I�CIII CRC who underwent curative surgery, tumor PIK3CA mutation was associated with shorter cancer-specific survival. Such adverse effect of PIK3CA mutation on prognosis was consistent across most strata of clinical and tumoral predictors of patient outcome. Interestingly, this adverse effect was mainly limited to patients with KRAS wild-type tumors In conclusion, we document that concomitant detection of KRAS, BRAF and PIK3CA mutations and evaluation of loss of PTEN expression in mCRC patients has remarkable clinical implications by increasing the ability to predict the Ginkgolide-J outcome to EGFR-targeted therapies. In light of the nature of our patient series, the most reliable indicator of the predictive value of biomarker is objective tumor response. Interpretation of survival analyses should indeed take into account a possible limitation due to patients treated with mixed previous line of chemotherapy including a 10% of patients treated with first-line cetuximab monotherapy. On the other hand, the study of such patients represents a unique opportunity to ascertain the predictive value of a given biomarker without the influence of chemotherapy, either concurrent or previous, as well as of selection exerted by other treatments. In light of these considerations, we propose here a new algorithm for deciding the clinical use of EGFR-targeted monoclonal antibodies that is based on objective response rates. This novel approach deserves validation in prospective studies with cetuximab- or panitumumab-based therapies in mCRC prior to have an impact as clinical practicechanging.